Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. We conducted RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases were compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstratesa distinct immune response pattern in TBM, with significant increase inboth canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicatesthat the ventricular profile representsbrain injury whereas the lumbar profile representsprotein translation and cytokine signalling. Together, transcriptomic analysis shows thatdisease processes differ between the periphery and the central nervous system, and within brain compartments.